While approximately 60% of depressed patients experience an antidepressant response after sleep deprivation (SD), the clinical utility of this intervention has been limited by the fact that most patients relapse after a night of recovery sleep. The purpose of this study is to test two possible clinical applications of SD: (1) its ability to hasten the onset of the action of antidepressant medication, and (2) its ability to potentiate the action of antidepressant medication in partially-responsive patients. Because patients cannot be blind to the fact that they are being sleep deprived, it is difficult to design an adequate control condition for SD. There is literature to indicate that sleep deprivation in the second half of the night (late sleep deprivation, or LSD) is a more active treatment than sleep deprivation in the first half of the night (early sleep deprivation, or ESD). Thus, in addition to the goals noted above, these experiments also test the utility of using ESD as a control condition for LSD in SD research. Patients in both protocols are randomly assigned to ESD or LSD, and follow that schedule of SD for two nights in a row during each of two successive weeks. There is extensive, systematic monitoring of mood and behavior prior to the SD, and for three weeks after the last SD. In the first protocol, patients are drug-free at the beginning of the study, and are started on fluoxetine 20 mg four days before their first night of SD. Twenty-one patients have completed the protocol, eleven in the LSD condition and thirteen in the ESD condition. Preliminary analyses of the data indicate that there are no significant differences between the ESD group and the LSD group in the course of their response to fluoxetine. Therefore, at this point there is no indication that SD can be used to hasten the onset of the action of fluoxetine. All patients accepted in the second protocol have been on a stable regimen of antidepressant medication for at least eight weeks, and they are continued on this regimen throughout the study. Twenty-six patients have completed the protocol, fourteen in the ESD condition and twelve in the LSD condition. There do not appear to be significant differences in the response of the two groups, so ESD does not appear to be an adequate control condition for LSD in this population. However, the SD treatment does appear to decrease significantly the subjects' Hamilton Depression Rating Scale scores. This effect remains significant even after patients whose scores dropped 30% or more upon entry into the study (so-called "placebo responders") are excluded. Therefore, it appears that SD may potentiate the efficacy of antidepressant medications. Before and after the nights of SD, blood is drawn to monitor levels of TSH, T-3, cortisol, and prolactin. These data are currently being analyzed.